VCV000051031.25 - ClinVar

NM_000492.4(CFTR):c.-226G>T

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(1); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.-226G>T

Variation ID: 51031 Accession: VCV000051031.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117479869 (GRCh38) [ NCBI UCSC ] 7: 117119923 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 4, 2016	Sep 16, 2024	Apr 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.-226G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000007.14:g.117479869G>T
NC_000007.13:g.117119923G>T
NG_016465.4:g.19086G>T
NG_056120.2:g.3899G>T
LRG_663:g.19086G>T
LRG_663t1:c.-226G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000007.14:117479868:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00359 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00359

1000 Genomes Project 30x 0.00406

The Genome Aggregation Database (gnomAD) 0.00422

Trans-Omics for Precision Medicine (TOPMed) 0.00456

Links

ClinGen: CA325805 dbSNP: rs73717525 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		-	-	GRCh38 GRCh37	3832	5210
LOC111674463	-	-	-	GRCh38	-	79

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Apr 26, 2023	RCV000043700.10
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Apr 11, 2024	RCV000727142.20

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 04, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601073.4 First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024	Publications: PubMed (11) PubMed: 31665830‚ 17678620‚ 11168023‚ 18832460‚ 21948798‚ 10204861‚ 12939925‚ 15025720‚ 11523757‚ 26656651‚ 25266997 Comment: In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 31665830 (2020), 18832460 (2008), 11168023 (2001), 10204861 (1999)). Functional studies … (more) In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 31665830 (2020), 18832460 (2008), 11168023 (2001), 10204861 (1999)). Functional studies indicate this variant may impact promoter activity but not at a significant difference from the wild type (PMIDs: 17678620 (2007), 21948798 (2012)). The frequency of this variant in the general population, 0.014 (117/8656 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Likely benign (Apr 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000071713.7 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024
Uncertain significance (Apr 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001810789.5 First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate decreased Sp1 and USF DNA-binding and decreased transcriptional activity in one study that utilized a core promoter construct, but the associated … (more) Published functional studies demonstrate decreased Sp1 and USF DNA-binding and decreased transcriptional activity in one study that utilized a core promoter construct, but the associated transcriptional activity was not significantly different from wild type in a second study that utilized a full-length promoter construct (PMID: 17678620, 21948798); Identified in individuals with cystic fibrosis in published literature, but in whom a second CFTR variant was either not detected or not specified (PMID: 10204861, 31665830, 18832460); Describes a nucleotide substitution 226 basepairs upstream of the ATG translational start site in the 5' untranslated region (UTR); Also known as c.-94G>T; This variant is associated with the following publications: (PMID: 12939925, 26656651, 11168023, 31665830, 18832460, 21948798, 10204861, 37313453, 17678620) (less)
Uncertain significance (Jun 15, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000706119.2 First in ClinVar: Mar 30, 2018 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR Number of individuals with the variant: 20 Sex: mixed
Uncertain significance (Dec 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003831632.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Benign (Aug 12, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002736623.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Nov 15, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004565191.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024

Comment:

In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 31665830 (2020), 18832460 (2008), 11168023 (2001), 10204861 (1999)). Functional studies indicate this variant may impact promoter activity but not at a significant difference from the wild type (PMIDs: 17678620 (2007), 21948798 (2012)). The frequency of this variant in the general population, 0.014 (117/8656 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

Published functional studies demonstrate decreased Sp1 and USF DNA-binding and decreased transcriptional activity in one study that utilized a core promoter construct, but the associated transcriptional activity was not significantly different from wild type in a second study that utilized a full-length promoter construct (PMID: 17678620, 21948798); Identified in individuals with cystic fibrosis in published literature, but in whom a second CFTR variant was either not detected or not specified (PMID: 10204861, 31665830, 18832460); Describes a nucleotide substitution 226 basepairs upstream of the ATG translational start site in the 5' untranslated region (UTR); Also known as c.-94G>T; This variant is associated with the following publications: (PMID: 12939925, 26656651, 11168023, 31665830, 18832460, 21948798, 10204861, 37313453, 17678620)

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico.	Zeiger AM	Pediatric pulmonology	2020	PMID: 31665830
Cystic fibrosis on the African continent.	Stewart C	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26656651
Novel personalized therapies for cystic fibrosis: treating the basic defect in all patients.	Amaral MD	Journal of internal medicine	2015	PMID: 25266997
Nucleosome occupancy reveals regulatory elements of the CFTR promoter.	Ott CJ	Nucleic acids research	2012	PMID: 21948798
WGA allows the molecular characterization of a novel large CFTR rearrangement in a black South African cystic fibrosis patient.	des Georges M	The Journal of molecular diagnostics : JMD	2008	PMID: 18832460
First functional polymorphism in CFTR promoter that results in decreased transcriptional activity and Sp1/USF binding.	Taulan M	Biochemical and biophysical research communications	2007	PMID: 17678620
Novel CFTR mutations in black cystic fibrosis patients.	Feuillet-Fieux MN	Clinical genetics	2004	PMID: 15025720
Molecular diagnosis of cystic fibrosis in South African populations.	Goldman A	South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde	2003	PMID: 12939925
The S549R (T-->G) cystic fibrosis gene mutation.	Dawson KP	Journal of tropical pediatrics	2001	PMID: 11523757
The molecular basis of cystic fibrosis in South Africa.	Goldman A	Clinical genetics	2001	PMID: 11168023
First putative sequence alterations in the minimal CFTR promoter region.	Romey MC	Journal of medical genetics	1999	PMID: 10204861
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
click to load more click to collapse

Text-mined citations for rs73717525 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.-226G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs73717525 ...